Normal tissue develops, and is maintained by, processes of cell division and cell death. In many diseases, such as cancer, diabetes mellitus Type I, and autoimmune disease, the normal balance between cell division and cell death is disrupted, causing either a rapid growth of unwanted and potentially dangerous cells, and/or a loss of cells essential to maintaining the functions of tissue.
Inappropriate cell division or cell death can result in serious life-threatening diseases. Diseases associated with increased cell division include cancer and atherosclerosis. Disease resulting from increased cell death includes AIDS, neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa), aplastic anemia, atherosclerosis (e.g., myocardial infarction, stroke, reperfusion injury), and toxin induced liver disease.
It has recently been discovered that uncoupling protein (“UCP”) is present in the membranes of cells other than in the mitochondria. For instance, it has been discovered that UCP is present in the plasma membrane of rapidly dividing cells. It was found that the UCP in the plasma membrane plays an important role in the signal processes which determine whether a cell will undergo cellular division, cellular differentiation, or cellular death. This finding has important implications for treating diseases associated with excessive cellular division, aberrant differentiation, and premature cellular death, e.g., for the treatment of cancers, autoimmune disease, degenerative diseases, regeneration, etc.
Several cell surface proteins have previously been identified as cell death proteins. These proteins are believed to be involved in initiating a signal, which instructs the cell to die. Cell death proteins include, for example, Fas/CD95 (Trauth, et al., Science, 245:301, 1989), tumor necrosis factor receptors, immune cell receptors such as CD40, OX40, CD27 and 4-1BB (Smith, et al., Cell, 76:959, 1994), and RIP (U.S. Pat. No. 5,674,734). These proteins are believed to be important mediators of cell death. These mediators, however, do not always instruct a cell to die. In some cases, these mediators actually instruct a cell to undergo cell division. The intracellular environment, and particularly the status of the proton motor force and the source of fuel for mitochondrial metabolism, determines whether stimulation of the cell death protein will lead to a signal for death or cell division (see, e.g., co-pending U.S. patent application Ser. No. 09/277,575, incorporated herein by reference).
UCP can regulate cell division by manipulating the manner in which the cell processes and utilizes energy. It has been discovered that UCP is normally present on the plasma membrane of rapidly dividing cells, but is not typically found on the plasma membrane of growth-arrested or chemotherapy-resistant tumor cells. These findings have important implications on the ability to regulate cell division as well as sensitivity and resistance to chemotherapeutic agents.
It is commonly observed in treating cancers, that initial treatments, such as with chemotherapy and/or radiation therapy, are effective to destroy significant numbers of tumor cells, only to leave behind a small number of tumor cells that are resistant to the treatment, which then multiply to form newly detected tumors that are increasingly resistant to treatment as new rounds of therapy are tried. The growing popularity of “cocktails” of chemotherapy drugs has given rise to multidrug resistant (“MDR”) tumor cells, which are ever more difficult to destroy. Drug sensitive tumor cells, under the selective pressure of treatment with drugs, develop into drug resistant versions of the same tumor cell type. Drug resistance, either acquired or inherent, is the leading cause of death in cancer. Methods for dealing with MDR tumor cells have been proposed, but without practical, clear clinical success at entirely eliminating such cells and providing a cure for patients with MDR tumors. For example, in Lampdis and Priebe U.S. Pat. No. 6,670,330, entitled: “Cancer Chemotherapy with 2-Deoxy-D-Glucose”, incorporated herein in its entirety by reference, a class of glycolytic inhibitors are described for use in combination with standard chemotherapy protocols in treating solid tumors by attacking anaerobic cells a the center of the tumor. In Pizer, Townsend and Kuhajda U.S. Patent Publication No. 20020187534, published Dec. 12, 2002, entitled: “Treating cancer by increasing intracellular malonyl CoA levels,” incorporated herein in its entirety by reference, fatty acid metabolism is manipulated by inhibition of carnitine palmitoyltransferase-1, for example with etomoxir.